Swarm Defense: Immune-system mechanism may lead to new airway drug delivery

Bacteria are present in just about every breath we take. How the airway protects itself from infection from these bacteria has largely remained a mystery—until now. When bacteria are inhaled, exosomes, or tiny fluid-filled sacs, are immediately secreted from cells that directly attack the bacteria and also shuttle protective antimicrobial proteins from the front of the nose to the back along the airway, protecting other cells against the bacteria before they get too far into the body.

A Harvard Medical School research team at Massachusetts Eye and Ear describes this newly discovered mechanism in a report published online Nov. 12 in the Journal of Allergy and Clinical Immunology (JACI). The findings shed new light on our immune system and pave the way for developing drug delivery techniques that harness this natural transportation process from one group of cells to another.

“Similar to kicking a hornets’ nest, the nose releases billions of exosomes into the mucus at the first sign of bacteria, killing the bacteria and arming cells throughout the airway with a natural, potent defense,” said senior author Benjamin Bleier, HMS associate professor of otolaryngology and a sinus surgeon at Mass. Eye and Ear. “It’s almost like this swarm of exosomes vaccinates cells further down the airway against a microbe before they even have a chance to ‘see’ it.”

The JACI study was motivated by a perplexing previous finding from Bleier’s lab. In studies of sinus inflammation, researchers found that proteins in the cells of the nasal cavity were also present in patients’ nasal mucus. The team wanted to know why and how these proteins were moving from the cells into the nasal mucus, hypothesizing that exosomes had something to do with it.

The new findings described in the JACI study shed light on this process. When cells at the front of the nose detect a bacterial molecule, they trigger a receptor called TLR4, which stimulates exosome release. When that happens, an innate immune response occurs within five minutes. First, it doubles the number of exosomes released into the nose. Second, within those exosomes, a protective enzyme, nitric oxide synthase, also doubles in amount. As a well-known antimicrobial molecule, nitric oxide potently arms each exosome to defend against bacteria.

The exosome “swarm” gets assistance from another natural mechanism of the nose—mucociliary clearance, which sweeps the activated exosomes to the back of the nose, along with information from cells that have already been alerted to the presence of bacteria. This prepares the cells in the back of the nose to immediately fight off the bacteria, arming them with defensive molecules and proteins.

In their experiments described in the JACI report, Bleier’s team sampled patients’ mucus and grew their own cells in culture. They then simulated an exposure to bacteria and measured both the number and composition of the released exosomes. They found a doubling of both the number of exosomes and of antibacterial molecules after stimulation. The team then confirmed this finding in patients and further showed that these stimulated exosomes were as effective as antibiotics at killing the bacteria. Finally, the team showed that the exosomes were rapidly taken up by other epithelial cells, where they were able to “donate” their antimicrobial molecules.

Along with this new understanding of the innate immune system, the authors on the JACI papersuggest that their findings may have implications for new methods of delivering drugs through the airway to be developed. More specifically, as natural transporters, exosomes could be used to transfer inhaled packets of therapeutics to cells along the upper airway—and possibly even into the lower airway and lungs.

“The nose provides a unique opportunity to directly study the immune system of the entire human airway, including the lungs,” said Bleier.

Additional authors on the JACI report include Angela Nocera of Mass. Eye and Ear and Derrick Lin of HMS and Mass. Eye and Ear, Sarina Mueller of HMS, Mass. Eye and Ear and University of Erlangen-Nuremberg, Jules Sephan of MIT, Loretta Hing and Xue Han of Boston University, Philip Seifert of Schepens Eye Research Institute of Mass. Eye and Ear, Mansoor M. Amiji of Northeastern University, and Towia Libermann of HMS and Beth Israel Deaconess Medical Center.